RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation

• Published in: Cell research 2013-04, Vol.23 (4), p.552-564
• Main Authors: Lee, James T, Shan, Jing, Zhong, Jiayun, Li, Muyang, Zhou, Brenda, Zhou, Amanda, Parsons, Ramon, Gu, Wei
• Format: Article
• Language: English
• Subjects: 631/45/612/645; 631/67/581; 631/80/458/1733; 631/80/86; AKT; Apoptosis - genetics; Biomedical and Life Sciences; Cell Biology; Cell Line, Tumor; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation; Humans; Life Sciences; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; original-article; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; RNA, Small Interfering - genetics; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; Ubiquitination; 亚细胞定位; 化调; 基因介导; 泛素化; 活化; 磷脂酰肌醇-3
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2013.27

The PTEN tumor suppressor is a lipid phosphatase that has a central role in regulating the phosphatidylinositol-3- kinase （PI3K） signal transduction cascade. Nevertheless, the mechanism by which the PTEN activity is regulated in cells needs further elucidation. Although previous studies have shown that ubiquitination of PTEN can modulate its stability and subcellular localization, the role of ubiquitination in the most critical aspect of PTEN function, its phos- phatase activity, has not been fully addressed. Here, we identify a novel E3 ubiquitin ligase of PTEN, Ret finger pro- tein （RFP）, that is able to promote atypical polyubiquitinations of PTEN. These ubiquitinations do not lead to PTEN instability or relocalization, but rather significantly inhibit PTEN phosphatase activity and therefore modulate its ability to regulate the PI3K signal transduction cascade. Indeed, RFP overexpression relieves PTEN-mediated inhibi- tory effects on AKT activation; in contrast, RNAi-mediated knockdown of endogenous RFP enhances the ability of PTEN to suppress AKT activation. Moreover, RFP-mediated ubiquitination of PTEN inhibits PTEN-dependent ac- tivation of TRAIL expression and also suppresses its ability to induce apoptosis. Our findings demonstrate a crucial role of RFP-mediated ubiquitination in controlling PTEN activity.